Results Of Treatment For Patients With Hepatocellular Carcinoma By Conventional Transarterial Chemoembolization And Drug-Eluting Bead Transarterial Chemoembolization - Pham Trung Dung

Journal of military pharmaco-medicine n o 5-2019 177 RESULTS OF TREATMENT FOR PATIENTS WITH HEPATOCELLULAR CARCINOMA BY CONVENTIONAL TRANSARTERIAL CHEMOEMBOLIZATION AND DRUG-ELUTING BEAD TRANSARTERIAL CHEMOEMBOLIZATION Pham Trung Dung1; Nguyen Quang Duat2; Vu Van Khien3 SUMMARY Objectives: Hepatocellular carcinoma is high in prevalence and mortality rate. Palliative treatments of hepatocellular carcinoma include conventional transarterial chemoembolization and drug-eluting bead transarterial chemoembolization. This study aims to compare results of treatments by conventional transarterial chemoembolization and drug-eluting bead transarterial chemoembolization and to assess factors related to treatment outcomes between the 2 groups. Results: Tumor size reduction after 1 - 3 months in conventional transarterial chemoembolization group was 26.4% and drug-eluting bead transarterial chemoembolization group was 40.2%, significantly different (p = 0.048). Decreasing serum AFP level of conventional transarterial chemoembolization group was 36.7%, drug-eluting bead transarterial chemoembolization group was 50.2%, significantly different (p = 0.002). Average survival time of conventional transarterial chemoembolization group was 17.1 ± 1.3 months, drug-eluting bead transarterial chemoembolization group was 21.6 ± 1.3 months, significantly different (χ 2 = 7.1, p = 0.008). Side effects: Pain in the liver, fever, fatigue and nausea, vomitting for the conventional transarterial chemoembolization group were 73.7%, 30.9%, 42.5%, 2.0%, respectively, for the drug-eluting bead transarterial chemoembolization group 81.6%, 18.7%, 28.2%, 3.0%, respectively. The risk of death of the drug-eluting bead transarterial chemoembolization group was higher than that of drug-eluting bead transarterial chemoembolization group (p 20 ng/mL) (1.56 times); poorly cell differentiation (1.37 times), Okuda I (2.34 times), no tumor response after treatment (according to mRECIST) (1.54 times). Conclusion: Drug-eluting bead transarterial chemoembolization has a better therapeutic effect than conventional transarterial chemoembolization. However, the side effects of the 2 groups were still contradictory . Morphological characteristics of poorly differentiated tumor, serum AFP increased (> 20 ng/mL) before treatment, disease stage Okuda I, not respond soon hepatoma (according to mRECIST) are predictive factors which positively associated long-term survival results after treatment. * Keywords: Hepatocellular carcinoma; Conventional transarterial chemoembolization; Drug-eluting bead transarterial chemoembolization. 1. Construction Hospital 2. 103 Military Hospital 3. 108 Military Central Hospital Corresponding author: Pham Trung Dung (phamtrungdung82@yahoo.com) Date received: 10/04/2019 Date accepted: 20/05/2019 Journal of military pharmaco-medicine n o 5-2019 178 INTRODUCTION Hepatocellular carcinoma (HCC) is one of the most common cancer that accounts for 95% of liver malignancy. HCC is the sixth in prevalence of cancer worldwide (fifth in Vietnam) and third in cancer-related deaths [1, 5]. HCC has poor prognosis with 5 years survival rate at 5% [6]. In 2002, transarterial chemoembolization (TACE) was approved as an alternative treatment for HCC patients who were not suitable for curative treatments. Conventional transarterial chemoembolization (cTACE) was defined as injection of anti- cancer drug with or without lipiodol to embolize nourishing arteries of tumors. Drug-eluting bead transarterial chemoembolization (DEB-TACE) was developed based on cTACE. The method used drug-loaded beads to control, maintain high chemical concentration inside tumors and to reduce chemical concentration in the cardiovascular system. In Vietnam, cTACE was widely performed in cardiovascular intervention centers, DEB-TACE was mainly performed in large centers. Data on comparison of treatment results and side effects between these two methods was limited. Therefore, we conducted this study with aims to: - To evaluate the efficacy of cTACE and DEB-TACE in treating HCC patients. - To evaluate safety and to identify prognostic factors between two groups. SUBJECTS AND METHODS 1. Subjects. 280 HCC patients were divided into 2 groups: cTACE (n = 121) and DEB-TACE (n = 159) at Deparment of Gastroenterology, 103 Military Hospital and Deparment of Gastroenterology, 108 Military Central Hospital from May 2014 to December 2017. * Inclusion criteria: - HCC-diagnosed patients based on the following criteria (Guidelines for diagnosis of Vietnam Ministry of Health in 2012) [4]: + Confirmed diagnosis on histopathology. + Typical images on CT-scan with contrast injection or MRI with magnetic blocker + AFP > 400 ng/mL. + Typical image on abdominal CT-scan with contrast or MRI with magnetic resistance + AFP is higher than normal (less than 400 ng/mL) + HBV or HCV infection. - Inclusion criteria for treatments by TACE and DEB-TACE (the Barcelona Clinic Liver Cancer (BCLC) stage B) [7]: + No portal vein thrombosis. + No arterioportal shunts in the liver. + Agreed to participate the study. * Exclusion criteria: + Child-Pugh class C, ECOG score 3 - 4. + Ongoing esophageal varices hemorrhage. + Coagulation disorder: Prothrombin < 60%; platelets < 50 G/L. + The patient was intervened to treat tumors before. + Patients failed to follow-up. + Comorbid diseases (heart failure, renal failure, respiratory failure...). + Elderly patients. + Pregnant or breastfeeding women. Journal of military pharmaco-medicine n o 5-2019 179 2. Methods. Non-randomized controlled clinical trial. * Interventional procedures: Similar to conventional vascular embolization. - cTACE: Lipiodol dose in mL was equal to the maximum diameter of the tumor. Doxorubicin dose was calculated in mL (doxorubicin 2 mg/mL) and was equal to 1.5 times the size of the biggest tumor in cm (1.5 mL of doxorubicin per 1 cm of tumor diameter). We created an emulsion of doxorubicin - lipiodol by using two syringes 20 mL and 10 mL connected to a three-way stopcock. Then, we identified the arteries that artery-clogging pumps feeding the tumor by spongel (spongel was mixed with a water-soluble contrast agent and was pumped into the catheter by a 1 mL syringe until it stopped at the end of the catheter). The process was closely monitored to prevent spongel reflux into arteries that nourish normal liver tissues. - DEB-TACE: The procedure was similar to conventional vascular embolization. Doxorubicin (Ebewe, Austria) was loaded into DC-Beads (Biocompatibles, United Kingdom) 90 - 120 minutes before the interventions. - Dose: Doxorubicin 50 - 150 mg/ intervention based on general recommendation, used one or two sizes of DC-Beads (100 - 300 µm, 300 - 500 µm, 500 - 700 µm). * Post-treatment variables: Clinical response to treatments, tumor shrinkage evaluated by mRECIST, serum AFP, survival time, side effects. * Statistical analysis: We used SPSS 20.0 for statistical analysis. RESULTS 280 HCC patients were divided into 2 groups: cTACE (n = 121) intervene tumor 346 times and DEB-TACE (n = 159) intervene tumor 305 times. 1. The characteristics of patients in the cTACE and DEB-TACE groups. Table 1: Characteristics cTACE DEB-TACE p n = 121 % n = 159 % Age group ≤ 30 years 3 2.5 3 1.9 0.7 31 - 50 years 22 18.2 29 18.2 51 - 70 years 74 61.2 95 59.7 > 70 years 22 18.2 32 20.1 Averange age 59.37 ± 12.2 60.52 ± 12.7 0.6 Gender Male 115 95.0 148 93.1 0.34 Female 6 5.0 11 6.9 Journal of military pharmaco-medicine n o 5-2019 180 Clinical symptoms Pain in the liver 90 74.4 131 82.4 0.14 Tiredness 65 53.7 69 43.4 0.09 Digestive disorders 27 22.3 26 16.4 0.2 Weight loss 28 23.1 48 30.2 0.2 Hepatomegaly 65 53.7 66 41.5 0.06 Ascites 1 0.8 2 1.3 0.6 Subclinical symptoms Serum AFP (ng/mL) AFP ≤ 20 40 33.0 59 37.2 0.48 20 < AFP < 200 29 24.0 43 27.0 AFP ≥ 200 52 43.0 57 35.8 Cell differentiation Poor 3 11.5 16 15.0 0.79 Moderate 16 61.5 58 54.2 High 7 27.0 33 30.8 Diameter < 8 cm 61 50.4 75 47.2 0.5 ≥ 8 cm 60 49.6 84 52.8 Average tumor size (cm) 9.04 ± 4.49 9.28 ± 4.20 0.25 Child-Pugh A 115 95.0 154 96.9 0.44 B 6 5.0 5 3.1 Okuda I 70 57.9 99 62.3 0.46 II 51 42.1 60 37.7 The characteristics of patients in the cTACE group and the DEB-TACE group were mostly identical. 2. Post-treatment tumor response and serum AFP. Table 2: Tumor response 1 - 3 months after the first treatment. Tumor response evaluated by RECIST cTACE DEB-TACE p p1,2 - 3,4 n = 121 % n = 159 % Complete response (1) 16 13.2 32 20.1 0.11 0.048 Partial response (2) 16 13.2 32 20.1 Stable disease (3) 52 43.0 59 37.2 Progressive disease (4) 37 30.6 36 22.6 DEB-TACE had higher rates of complete response and partial response than cTACE (p = 0.048). Journal of military pharmaco-medicine n o 5-2019 181 Figure 1. Serum AFP between two groups. DEB-TACE had a significantly better rate of serum AFP reduction compared to cTACE, the difference was statistically significant (p = 0.002). 3. Side effects. Table 3: Side effects after treatment between two groups. Symptoms after intervention cTACE DEB-TACE p n = 346 % n = 305 % Liver pain 255 73.7 249 81.6 0.016 Fever 107 30.9 57 18.7 0.001 Fatigue 147 42.5 86 28.2 0.001 Nausea, vomitting 7 2.0 9 3.0 0.45 Patients treated by cTACE had lower proportion of liver pain and higher proportion of fever and fatigue after treatment compared with DEB-TACE group. 4. Survival time after treatments. At the end of our research, there were 176 deaths and 104 patients were followed. Average follow-up time was 14.3 months. Table 4: Overall survival time (OS) and progressive-free survival time (PFS). Mean survival time (95% CI) p Cummulative survival rates (%) 1 year 2 year 3 year OS cTACE 17.1 ± 1.3 0.008 52.1 25.0 13.9 DEB-TACE 21.6 ± 1.3 65.3 42.6 24.1 PFS cTACE 12.7 ± 1.3 0.001 30.2 18.6 18.6 DEB-TACE 17.7 ± 1.4 53.0 33.7 10.2 Mean survival time in the DEB-TACE group was statistically longer than that in cTACE group (χ2 = 7.1, p = 0.008). Decrease No change Increase Journal of military pharmaco-medicine n o 5-2019 182 5. Factors related to survival time of HCC patients. We analyzed several factors that could be related to mortality of HCC patients treated by cTACE or DEB-TACE. The results was shown in figure 2. Figure 2: Hazard ratio of factors related to survival rate. Histopathology of poor differentiation, serum AFP > 20 ng/mL, Okuda class I, unresponsive liver tumors (based on mRECIST) were positive predictive factors of mortality in patients treated by cTACE and DEB-TACE. DISCUSION 1. Tumor response after treatment. Tumor response is an important prognostic factor in the treatment of HCC. Tumor shinkage is related to patient's prognosis and survival time. Currently, the European Association for the Study of the Liver (EASL) recommends using mRECIST to assess post-treatment response. The classification includes: Complete response, partial response, stable disease and progressive disease. Our results showed that cTACE group had better tumor response in 1 - 3 months after treatment: complete response was 13.2%, partial response was 13.2%, stable disease was 43%, progressive disease was 30.6%; DEB-TACE group rates of response was 20.1%, 20.1%, 37.2% và 22.6%, respectively. Our results showed that DEB-TACE was better than cTACE, especially in post-treatment tumor response. However, patients selection, the time of treatment intervention and the experience of the physician... are related to the efficacy Journal of military pharmaco-medicine n o 5-2019 183 of treatments. Thai Doan Ky performed DEB-TACE in the patients with HCC and reported that the tumor response were quite high: Complete response was 32.4%, partial response was 40.0%, stable disease was 17.1%, progressive disease was 10.5% [2]. Assessing tumor response after treatments by DEB-TACE required long-term follow- up. A study by Varela M et al stated that the rate of tumor response at 1 - 6 months after treatment was 75% [8]. A multicenter randomized clinical trials by PRECISION V in Europe reported: response rate, complete response and tumor control rate in the DEB-TACE group were all higher than cTACE group [9]. 2. Serum AFP after treatment. Serum AFP was a common tumor marker and was widely used for diagnosis, follow-up and prognosis after treatment. Decreased level of serum AFP showed good prognosis and was usually associated with tumor shrinkage. Changes of serum AFP depended on treatment methods of HCC. In our research (figure 1), 3 months after treatments, the proportions of patients with decreased, no change and increased level of serum AFP were: 36.7%, 25.1% and 38.2%, respectively; these rates in the DEB-TACE group were 50.2%, 17.4% and 32.5%, the differences were statistically significant (p < 0.05). A study by Song M.J et al (2012), the proportion of patients with decreased AFP in the DEB-TACE group was statistically higher than cTACE group (77.4% compared to 45.4%, p = 0.011) [10]. Le Van Truong performed cTACE for 108 HCC patients with an average tumor size of 9.4 cm, the results showed that only 30% had decreased serum AFP, 50% remained unchanged and 15% had increased serum AFP after treatment [1]. The Thai Doan Ky’s study on 105 patients treated by DEB-TACE reported 50% of patients had decreased serum AFP, 39% remained unchanged and 13.3% had increased serum AFP after treatment. 3. Side effects after treatment. Side effects after treatment were seen in both groups. In our research (table 3), the rates of patients with fever and fatigue were lower in the DEB-TACE group. However, liver pain was more prominant in the DEB-TACE group. The side effects found in our research were similar to other research in Vietnam [1, 2]. 4. Survival time after treatments. Survival time is an important indicator to evaluate the efficacy of treatment for patients with HCC. The overall survival and average life time depend on many objective and subjective factors. Characteristics of tumors, cirrhosis status, patient's condition and treatment methods are related to the patient's lifetime. In our study, 1-year, 2-year and 3-year cummulative survival rates of cTACE was 52.1%, 25.0%, 13.9% and DEB-TACE was 65.3%, 42.6%, 24.1%. Mean survival time of the cTACE group was 17.1 ± 1.3 months and DEB-TACE group was 21.6 ± 1.3 months, the difference was statistically significant (χ2 = 7.1, p = 0.008). The mean PFS time of cTACE group was 12.7 ± 1.3 months and DEB-TACE group Journal of military pharmaco-medicine n o 5-2019 184 was 17.7 ± 1.4 months, the difference was statistically significant (χ2 = 11.11, p = 0.001). Le Van Truong performed cTACE on 108 HCC patients and reported that the mean survival time was 13 months, 1-year, 2-year and 3-year survival rates were 55.6%, 21.3% and 11.2%, respectively [1]. Most patients in this research had large liver tumors accompanied by cirrhosis. Thai Doan Ky's study on 105 patients with HCC treated by DEB-TACE showed mean survival time at 27.9 ± 1.6 months, 1-year, 2-year and 3-year cummulative survival rates were 72.9%, 54.4% and 41.3%, respectively [2]. A meta-analysis done by Huang K (2014) from 7 studies on 700 patients reported that DEB-TACE had significantly higher 1-year, 2-year and 3-year survival rates compared with the group cTACE (p = 0.007, p = 0.0003 and p = 0.01, respectively) [11]. 5. Factors related to survival time of two groups: cTACE and DEB-TACE. Multivariate analysis by Cox regression model showed that mortality risk of cTACE group was higher than DEB-TACE group. Comparing with DEB-TACE, cTACE was significantly associated to mortality in patients having elevated serum AFP (1.56 times); poor differentiation (1.37 times), Okuda class I (2.34 times), nonresponsive tumors after first treatment based on mRECIST (1.54 times). Facciousso (2016) evaluated prognostic factors of treament outcomes in 104 patients treated by cTACE and 145 patients treated by DEB-TACE (all patients had BCLC class A or B tumors). The study showed that cTACE had significant association with survival rate in patients with high level of AFP, malignancy in both liver lobes and portal hypertension. The hazard ratios were 2.29, 2.5 and 1.75, respectively [12]. A study conducted by Song et al showed that AFP < 200 ng/mL was an independent factor of survival rate [10]. CONCLUSIONS - Patients treated by DEB-TACE had better tumor response, serum AFP response and survival time than cTACE. 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